Search

Adjuvant endocrine therapy is a gold standard in early-stage, hormone receptor positive breast cancer. In postmenopausal women, aromatase inhibitors (AIs) are associated with improved outcome compared to tamoxifen monotherapy. Differences in the toxicity profiles of these drugs are described; however, little is known about whether the risk of adverse events changes over time. Sequential reports of large, randomized, adjuvant endocrine therapy trials comparing AIs to tamoxifen were reviewed. Data on pre-specified adverse events were extracted including cardiovascular events, bone fractures, cerebrovascular disease, endometrial cancer, secondary malignancies excluding breast cancer, venous thrombosis and death without recurrence. Odds ratios (ORs) were calculated for each adverse event at each time over the course of follow-up. The change in the ORs for adverse events over time was evaluated using weighted linear regression. Analysis included 21 reports of 7 trials comprising 30,039 patients and reporting outcomes between 28 and 128 months of follow-up. Compared to tamoxifen, AIs use was associated with a significant reduction in the magnitude of increased odds of bone fracture over time (β = − 0.63, p = 0.013). There was a non-significant decrease in the magnitude of reduced odds of secondary malignancies over time (β = 0.448, p = 0.094). The differences in other toxicity profiles between AIs and tamoxifen did not change significantly over time. The increased risk of bone fractures associated with adjuvant AIs falls over time and after discontinuation of treatment. Differences in other toxicities between AIs and tamoxifen do not change significantly over time including a persistently elevated risk of cardiovascular events.

533 Background: Early stage breast cancer is a curable disease with the majority of patients dying of causes other than breast cancer. The influence of these competing risks of death on the interpretation of Kaplan-Meier(KM)-based analyses such as those performed by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) are unknown. Methods: We searched the Clinical Trial Service Unit and Epidemiological Studies Unit website at Oxford University to identify all meta-analyses published by the EBCTCG between 2005 and 2018. Studies were included if they contained KM curves with risk estimates for either breast cancer mortality and/or breast cancer recurrence. The potential influence of competing risks was estimated using a validated multivariate linear model that predicts the amount that the KM risk estimates are biased relative to outcome risk measured with the cumulative incidence function (CIF). Results: The initial search identified 14 analyses published by the EBCTCG with 10 of the 14 studies (71%) susceptible to competing risk bias cited both the number of events of interest and competing events. Eight of the ten studies (80%) had a relative difference between the KM estimate and the competing risk adjusted estimate of more than 10% while 2 of 10 (20%) had a difference of less than 10%. The relative difference between the KM and adjusted estimates was 28.4% for local recurrence, 16.8% for distant recurrence, and 6.7% for breast cancer-specific mortality. There was 2.2% difference between KM and adjusted analyses between 0-4 years and 18.9% beyond 10 years of follow up. Use of KM and CIF-based analysis did not influence treatment effect in the majority of included studies. Conclusions: This study provides estimates for the overestimation of risk in Kaplan-Meier analyses resulting from failure to address competing risk bias. CIFs are more appropriate to measure outcome risk over time and should be used especially for long-term follow-up studies and for analysis of rare events.

Identification of membrane proteins expressed exclusively on tumor cells is a goal for cancer drug development. The receptor tyrosine kinase-like orphan receptor type 1 and 2 (ROR1/2), are type-I transmembrane proteins expressed in cancer but not in adult normal tissue. Here, we explore the prognostic role ROR1/2 expression on patient outcome.A systematic search of electronic databases identified publications exploring the effect of ROR1/2 on overall survival (OS). Hazard ratios (HR) from collected data were pooled in a meta-analysis using generic inverse-variance and random effects modeling. Subgroup analyses were conducted based on disease site or tumor type.Twenty five studies met the inclusion criteria. ROR1 was associated with worse overall survival (HR 2.13, 95% confidence interval (CI) 1.62-2.80; P 0.001) with subgroup analysis showing the strongest association between ROR1 and OS was in lung cancer. There was no significant difference between solid tumors and hematological malignancies (HR 2.15, 95% CI 1.52-3.06 vs. HR 2.02, 95% CI 1.46-2.84; subgroup difference P = 0.80). ROR2 was also associated with worse OS (HR 1.84, 95% CI 1.43-2.38; P 0.001). There was no significant difference between disease sites although the highest association seen was in head and neck cancers (HR 3.19, 95% CI 1.13-8.97) and the lowest in gynecological cancers (HR 1.19, 95% CI 0.71-2.00; subgroup difference P = 0.10).ROR1 and ROR2 expression is associated with adverse outcome in several tumors. ROR1/2 warrants study as a target for developmental therapeutics.

The concept of “big data” research—the aggregation and analysis of biologic, clinical, administrative, and other data sources to drive new advances in biomedical knowledge—has been embraced by the cancer research enterprise. Although much of the conversation has concentrated on the amalgamation of basic biologic data (e.g., genomics, metabolomics, tumor tissue), new opportunities to extend potential contributions of big data to clinical practice and policy abound. This article examines these opportunities through discussion of three major data sources: aggregated clinical trial data, administrative data (including insurance claims data), and data from electronic health records. We will discuss the benefits of data use to answer key oncology practice and policy research questions, along with limitations inherent in these complex data sources. Finally, the article will discuss overarching themes across data types and offer next steps for the research, practice, and policy communities. The use of multiple sources of big data has the promise of improving knowledge and providing more accurate data for clinicians and policy decision makers. In the future, optimization of machine learning may allow for current limitations of big data analyses to be attenuated, thereby resulting in improved patient care and outcomes.

Background Palbociclib, ribociclib and abemaciclib have all been approved in combination with endocrine therapy in hormone-receptor positive, HER2 negative metastatic breast cancer. While the efficacy of these drugs appears similar, differences in safety and tolerability are apparent. Methods We searched PubMed and ASCO, ESMO and SABCS proceedings to identify randomized trials of palbociclib, ribociclib and abemaciclib. Data on common and serious adverse events (AE) were extracted for each approved drug. The odds ratio for each AE and the hazard ratio for progression-free survival were calculated relative to endocrine therapy alone. A network meta-analysis was then performed for each endocrine therapy backbone (aromatase inhibitor (AI) or fulvestrant) to compare ribociclib and abemaciclib to palbociclib. Results 8 trials were included in the analysis and comprised 2799 patients receiving cyclin-dependent kinase 4/6 inhibitors palbociclib: 873 patients; ribociclib: 1153 patients; abemaciclib: 773 patients. In 5 trials (1524 patients), the endocrine therapy backbone was an AI and in 3 trials (1275 patients) it was fulvestrant. Compared to palbociclib, ribociclib and abemaciclib showed significantly lower grade 3–4 neutropenia, but significantly higher GI toxicity. Treatment discontinuation was higher with abemaciclib than other drugs. Efficacy of the 3 drugs was similar. Compared to palbociclib, for AI backbone, the HR for PFS for ribociclib was 0.98 and for abemaciclib 1.02. For fulvestrant backbone, the HR were 0.88 and 0.93 respectively. Conclusions Palbociclib, ribociclib and abemaciclib have comparable efficacy, but differences in safety and tolerability. Abemaciclib has worse tolerability with significantly higher treatment discontinuation likely due to GI toxicity.

Purpose The addition of platinum agents to anthracycline and taxane-based chemotherapy in early-stage triple negative breast cancer (TNBC) patients improves pathological complete response (pCR). Long-term outcomes, such as disease-free survival (DFS) and overall survival (OS), have not been well-established. Methods A systematic literature review identified studies using platinum-based treatment in TNBC patients in the neoadjuvant or adjuvant setting with reportable long-term outcomes. Hazard ratios (HR) from collected data were pooled in a meta-analysis using generic inverse-variance and random effects modeling. Subgroup analyses were conducted based on treatment setting and study design. Results Fourteen studies comprising 3518 patients met the inclusion criteria. Median follow up was 56.2 months. All studies reported DFS and 9 studies (64%) reported OS. DFS was significantly better in platinum-based treatment (HR 0.71, 95% confidence interval (CI) 0.56–0.89; p = 0.03). However, OS was no different (HR 0.98, 95% CI 0.75–1.27; p = 0.87). There was a non-significant difference between platinum exposure in the adjuvant compared to neoadjuvant setting for both DFS (HR 0.75 vs 0.62, p = 0.43) and for OS (HR 0.90 vs 1.10, p = 0.58). The addition of platinum was associated with more thrombocytopenia and all-grade neuropathy and non-significant increases in neutropenia and grade 3–4 neuropathy. Conclusions Platinum-based treatment improves DFS but not OS. The reporting of toxicity was suboptimal, but in general adding platinum increased toxicity. The discordant effect of platinum-based treatment on DFS and OS suggest the potential development of platinum resistance and worse outcomes after recurrence. Platinum-based chemotherapy cannot be recommended in unselected patients with early TNBC.

Background Overuse of laboratory investigations is widely prevalent in hospitalized patients, leads to discomfort, and increases direct and indirect costs. Objective We implemented a simple, inexpensive, mindfulness strategy on our inpatient medical clinical teaching unit to reduce unnecessary laboratory orders through education, a forcing function, and daily structured laboratory "time outs." Methods On a 26-bed unit in an academic hospital center, the per-period laboratory costs per patient were compared pre- and postintervention using segmented regression analysis of an interrupted time series. Results The average cost per admitted patient decreased from $117 to $66, with an estimated savings of $50,657 over 985 admissions. After adjusting for fiscal period and the presence of our intervention, there was a significant reduction in the per-patient number of total tests, complete blood counts, and electrolyte panels performed ( P Conclusion This trainee-designed and -led intervention, centered around structured, mindfulness-based laboratory test ordering, was successful at decreasing the overuse of common daily blood work in hospitalized patients.

Cancer is a genetic disease resulting from germline or somatic genetic aberrations. Rapid progress in the field of genomics in recent years is allowing for increased characterization and understanding of the various forms of the disease. The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (octane) clinical trial, open at cancer centres across Ontario, aims to increase access to genomic sequencing of tumours and to facilitate the collection of clinical data related to enrolled patients and their clinical outcomes. The study is designed to assess the clinical utility of next-generation sequencing (ngs) in cancer patient care, including enhancement of treatment options available to patients. A core aim of the study is to encourage collaboration between cancer hospitals within Ontario while also increasing international collaboration in terms of sharing the newly generated data. The single-payer provincial health care system in Ontario provides a unique opportunity to develop a province-wide registry of ngs testing and a repository of genomically characterized, clinically annotated samples. It also provides an important opportunity to use province-wide real-world data to evaluate outcomes and the cost of ngs for patients with advanced cancer. The octane study is attempting to translate knowledge to help deliver precision oncology in a Canadian environment. In this article, we discuss the background to the study and its implementation, current status, and future directions.

Background Clinical practice guidelines (CPGs) are crucial to the practice of evidence-based medicine. Declared author financial conflicts of interest (FCOIs) are common in CPGs and have been associated with endorsement of treatment. Less is known about undeclared FCOIs. Methods The American Society of Clinical Oncology (ASCO) website was searched to identify all CPGs for systemic therapy published between August 2013 and June 2018. Data on self-reported author FCOIs and funding sources were extracted. The Open Payments database was then searched to identify compensation to CPG authors. Concordance between declared and undeclared but verified FCOIs was assessed with Cohen's kappa. Results For 26 CPGs, 314 nonduplicate authors were identified; 184 of these authors (59%) disclosed FCOIs. Among the remaining 130 authors, data in Open Payments were unavailable for 71 authors (non-US residents or authors affiliated with a nonprofit organization). Among the 59 authors who declared no FCOIs and for whom Open Payments data were available, 55 (93%) had received payment from industry. The kappa value for agreement between disclosed and verified FCOIs was 0.092. Among the 243 authors with FCOIs verifiable via Open Payments, 239 (98%) received payment from industry. Thirty-four authors (62%) received more than $1000 in nonresearch funding, and 19 (35%) received more than $5000. Among the 52 first and last authors, 44 (85%) received payment from industry; 14 of these payments (32%) were not declared. Conclusions FCOIs among authors of ASCO CPGs are common and are not disclosed by a substantial proportion of authors with Open Payments data. Improved transparency of FCOIs should become standard practice among CPG authors. Professional societies and journal editors need to create a mechanism to verify self-reported FCOIs.

Background Hematometrocolpos caused by an imperforate hymen is a common form of vaginal outflow obstruction. This is a rare pediatric anomaly that can present with atypical or vague symptomatology, such as abdominal pain or constipation or urinary retention in the setting of amenorrhea. It is essential to obtain a gynecologic history and inquire about menstrual cycles to properly evaluate a young female with such a common complaint as abdominal pain. Failure to perform a gynecologic examination in the emergency department setting may delay diagnosis and appropriate care for this rare condition, which can lead to serious complications. Case Report This case describes a 12-year-old female who presented to the emergency department with a complaint of abdominal pain and urinary symptoms. Because of the severity of the patient's pain on abdominal examination, we obtained a computed tomography scan of her abdomen and pelvis, which showed findings consistent with hematometrocolpos. Why Should an Emergency Physician Be Aware of This? Obstruction of the female genital outflow tract is a rare occurrence. Because abdominal pain is such a common complaint, not only in the pediatric emergency department but also in the outpatient setting, the diagnosis of hematometrocolpos may easily go undiagnosed for months or even years. Obtaining a complete gynecologic history is key when evaluating young females with abdominal pain or urinary retention. Early detection and timely management can prevent serious complications and long-term sequelae. This patient had a successful outcome and early surgical management of her hematometrocolpos which was caused by an imperforate hymen.

Objectives The US Food and Drug Administration licensed ezetimibe in 2002 because of its ability to lower low-density lipoprotein cholesterol levels, a surrogate marker for the risk of coronary artery disease. The negative results of the Effect of Ezetimibe Plus Simvastatin Versus Simvastatin Alone on Atherosclerosis in the Carotid Artery trial were published in 2008. Since then, we have seen 6 additional years without a landmark study in favor of ezetimibe. Furthermore, the new American Heart Association/American College of Cardiology guidelines (2013) now strongly downplay the use of nonstatin agents. We sought to determine whether ezetimibe use remains common in 2014 using a new cohort that we have created to teach residents how to perform clinically relevant research. Methods The McGill Teaching Unit Cohort is an anonymized prospective cohort study enrolling all patients admitted to the medical clinical teaching units of the Royal Victoria Hospital in Montreal, Quebec, Canada, as of 2014. Information collected includes the receipt of cholesterol-lowering medications and other important demographics. Results Of the 783 patients enrolled on the date of analysis, 331 (42.7%) were receiving treatment for hypercholesterolemia. Of these, 156 (47%) were receiving primary prophylaxis. Overall, 323 patients (98%) were receiving a statin, 17 patients (5.1%) were receiving ezetimibe, and 5 patients (1.5%) were receiving a fibrate. Users of ezetimibe were more likely to be active smokers than nonusers (6/17 vs 42/314, P = .01); however, there were no other significant differences between important covariates or recent low-density lipoprotein measurements. Conclusions Ezetimibe use remains common amongst medical inpatients despite a lack of evidence supporting its efficacy.

A 56-year-old woman with a new diagnosis of metastatic pancreatic cancer presents to the emergency room with generalised fatigue. The patient is afebrile, however, hypotensive and tachycardic. Physical examination shows diffuse lymphadenopathy. Initial laboratory tests indicate that the patient has hyperkalaemia, hypocalcaemia, with a high lactate dehydrogenase and high uric acid. The patient was also in renal failure. On the basis of the clinical presentation, the patient was diagnosed with spontaneous tumour lysis syndrome, despite the syndrome never having been reported in metastatic pancreatic cancer. The patient was treated appropriately with intravenous hydration, allopurinol and rasburicase. All laboratory abnormalities were corrected by day 3 of treatment.

The vast majority of melanoma-related deaths are due to disseminated malignancy. Many treated patients who are clinically disease-free will go on to relapse. Therefore, new prognostic tools must be developed to better assess metastatic potential and assist in patient management. Circulating tumor cells are a widely studied metastatic biomarker with promising prognostic utility, as the shedding of cells from the primary tumor into peripheral blood is a necessary step in disease dissemination. An assortment of technologies and techniques has been developed to isolate and detect circulating melanoma cells (CMCs), but a standardized method is yet to be established. It is the aim of this study to systematically review the diverse enrichment and detection methods of circulating tumor cells in cutaneous melanoma. A literature search yielded 351 articles, of which 74 were deemed eligible according to inclusion criteria, the primary requirement being the reporting of patient CMC positivity status stratified by the stage of melanoma. Pertinent studies were used to evaluate the advantages and disadvantages of each method. Additionally, we calculated the sensitivity and specificity of seven common melanoma-associated markers based on the available literature.